Painful stimuli evoke pain sensation as well as unpleasant emotional feelings, and the emotional responses should be considered as an essential part of the pain experience. Clinical observations indicate that the debilitating nature of persistent pain induced by tissue injury (inflammatory pain) and nerve injury (neuropathic pain) is related to the suffering or anxiety the pain induces. Both persistent pain induced hypersensitivity (including hyperalgesia: increased responsiveness to noxious stimuli, and allodynia: painful responses to innocuous stimuli) and accompanied negative emotion (such as anxiety, angry, worry, fear, aversion, and related memory) can be regulated by transcriptional, translational, and post-translational mechanisms. The MAP kinase family member ERK (extracellular signal-regulated kinase) plays an important role in intracellular signaling and is implicated in pain hypersensitivity via these regulatory mechanisms. In the parent grant (RO1 NS40698), we focus on the role of ERK activation in primary sensory and dorsal horn neurons associated with peripheral and central sensitization, inflammatory pain, and gene transcription. To extend our previous study, the aim of this Fogarty proposal is to assess the involvement of the ERK in persistent pain-induced negative emotion in the anterior cingulate cortex (ACC). The project will test the following hypotheses: 1) ERK is activated in the ACC neurons following pain-related emotional affect and persistent pain-induced hypersensitivity, 2) ERK activation leads to CREB phosphorylation and the expression of CRE-containing genes in the ACC, 3) ERK activation in the ACC contributes to the induction and maintenance of affective pain. A number of different approaches, including immunostaining, western blot, and in situ hybridization will be used to detect protein and mRNA expression. A formalin-induced conditioned place avoidance (F-CPA) animal model will be used to discriminate sensory and affective component of pain. These results should provide further insights into the role of an intracellular signal cascade in the generation of sensation and negative emotion of persistent pain.